Atherosclerosis is the leading cause of death in diabetic patients and occurs more frequently and prematurely. If one examines the known risk factors identified for atherosclerosis in large population studies, all of the factors are intensified in diabetics. Controversy exists, however, whether hyperglycemia alone is a risk factor for atherosclerosis in diabetic subjects. Cholesterol-rich plasma low density lipo-protein (LDL) are considered to be a risk factor in atherogenesis due to their selective retention in the intima of arteries and to the subsequent uptake and metabolism by intimal cells with ensuing intracellular accumulation of cholesterol esters. Evidences indicated that prolonged hyperglycemia may be associated with increased plasma LDL-cholesterol. Preliminary studies in our laboratory suggest that plasma LDL could be non-enzymatically glycosylated in vitro, and in vivo not only in diabetic subjects but also in normal subjects. We propose to test a hypothesis which attempts to integrate current knowledge concerning LDL structure and the pathophysiology of atherosclerosis in diabetic subjects. This hypothesis represents an attempt to account for atherosclerosis at a molecular level. A change in LDL structure by non-enzymatic glycosylation would lead to decreased metabolism through the "receptor dependent pathway" and to increased accumulation of LDL in plasma, or to increased removal through the "scavenger pathway" including blood monocytes and tissue macrophages, contributing to atherogenesis. This proposed study should clarify some of the factors responsible for the predisposition to atherosclerosis in diabetes. The result may provide better approaches to treatment of lipid disturbances in these conditions in an effort to prevent coronary and peripheral vascular disease.